Atrial natriuretic factor in hypertension: bioactivity at normal plasma levels

To ascertain whether small shifts in plasma atrial natriuretic factor (ANF) exerted biological effects in hypertension, we studied the renal, hemodynamic, and hormonal effects of ANF [human ANF-(99-126)] infused at a dose (0.75 pmol/kg/min for 3 hours) that would induce changes in plasma ANF confined to the normal, resting range, in a group of six young men with uncomplicated, mild essential hypertension. During ANF infusions, the patients excreted 11.8 +/- 2.0 mmol (mean +/- SEM) sodium more than during the time-matched placebo phase natriuresis (p less than 0.001, mean increase of 53% above placebo values). Urinary excretion of cyclic guanosine monophosphate rose to more than double (212%, p less than 0.001) placebo values. Plasma renin activity (0.4 +/- 0.05 vs. 0.9 +/- 0.12 nmol/l/hr, p less than 0.0001) and aldosterone concentrations (102 +/- 4 vs. 184 +/- 47 pmol/l, p less than 0.05) were clearly suppressed during administration of ANF. Plasma norepinephrine also fell significantly below placebo values (268 +/- 17 vs. 439 +/- 35 pg/ml, p less than 0.05). Urine volume, the excretion of electrolytes other than sodium, hematocrit, effective renal plasma flow, glomerular filtration rate, and filtration fraction were unaffected by ANF. Similarly, plasma concentrations of epinephrine, arginine vasopressin, adrenocorticotropic hormone, and cortisol were unchanged. Blood pressure and heart rate were unchanged. Minor perturbations in plasma ANF concentrations exert clear biological effects in patients with mild essential hypertension. These data suggest that such minor shifts in plasma ANF are of physiological relevance in mild hypertension and probably contribute to volume homeostasis in this condition.     

Differential pressor and renal vascular reactivity to angiotensin II in spontaneously hypertensive and Wistar-Kyoto rats

The suggestion has been made that the Okamoto strain of spontaneously hypertensive rats (SHR) shares some features with a subgroup of patients with essential hypertension, called nonmodulators. One feature of nonmodulators is a renal blood flow response to angiotensin II (ANG II) that is blunted on a high salt diet; the blunted renal vascular response is corrected by converting enzyme inhibition. Renal blood flow (electromagnetic flowmeter) and pressor responses to graded ANG II doses (5-300 ng) were assessed in 24 SHR and 24 Wistar-Kyoto rats (WKY) ingesting 1.6% Na. In comparison to WKY, blood pressure was higher in SHR (155 +/- 4 vs 106 +/- 2 mm Hg; p less than 0.001), renal blood flow was lower (6.9 +/- 0.5 vs 8.2 +/- 0.4 ml/min/g; p less than 0.05), and the pressor response to ANG II was enhanced, (p less than 0.0005) but the renal vascular response was blunted (p less than 0.005). Captopril (1-30 mg/kg) reduced blood pressure more in SHR than in WKY but increased renal blood flow similarly in both strains. The blunted renal vascular response to ANG II in SHR was reversed by captopril, but inhibition of converting enzyme in the kidney did not parallel systemic inhibition. Maximum blockade of converting enzyme in the kidney appears to require a larger captopril dose than is required for systemic inhibition. These results suggest that the renal blood supply in SHR also shares some of the characteristics of nonmodulators and that the action of captopril on the renal blood flow probably reflects reversal of inappropriate intrarenal ANG II formation.     

Opposite effects of enalapril and nitrendipine on natriuretic response to atrial natriuretic factor. Renal function evaluated with clearance studies in humans

In clearance studies, we analyzed the effect of Ca2+ entry blockade with nitrendipine treatment (20 mg b.i.d. for 4 days) and of converting enzyme inhibition with enalapril treatment (20 mg b.i.d. for 4 days) on renal response to atrial natriuretic factor (ANF) (25 micrograms bolus followed by an infusion of 0.03 microgram/kg/min for 90 minutes) in six healthy volunteers who were taking 300 mmol sodium daily. In a control study ANF was administered without Ca2+ entry blockade or converting enzyme inhibition. Natriuresis rose from 239 +/- 38 to 605 +/- 137 mumol/min in the control study (p less than 0.05), from 330 +/- 53 to 943 +/- 152 mumol/min with Ca2+ entry blockade (p less than 0.05), and from 236 +/- 22 to 344 +/- 39 mumol/min with converting enzyme inhibition (NS). ANF induced a rise in maximal free water clearance, inulin clearance, and in the excretion of multiple electrolytes except potassium. Fractional lithium reabsorption fell. In general, these effects were stronger during Ca2+ entry blockade and blunted during converting enzyme inhibition. p-Aminohippurate clearance tended to decrease during the control study (NS), remained constant during Ca2+ entry blockade, and decreased significantly when ANF was infused during converting enzyme inhibition (p less than 0.05 vs. control and vs. Ca2+ entry blockade study). Blood pressure was lowered by Ca2+ entry blockade and, to a somewhat greater extent, by converting enzyme inhibition, but ANF administration induced no additional fall except for a short-term drop during Ca2+ entry blockade.(ABSTRACT TRUNCATED AT 250 WORDS)     

Blood pressure control by the renin-angiotensin system in normotensive subjects. Assessment by angiotensin converting enzyme and renin inhibition.

BACKGROUND. The participation of the renin-angiotensin system in the control of blood pressure in normal, sodium-replete subjects is not clear. The use of a specific inhibitor of human renin should allow a better delineation of the importance of this system. METHODS AND RESULTS. Blood pressure responses were measured 1 hour after randomized, double-blind administration of the renin inhibitor Ro 42-5892 (600 mg p.o.) or the angiotensin converting enzyme inhibitor captopril (50 mg p.o.) in 20 healthy men on an ad libitum sodium diet. Effective inhibition of the renin-angiotensin system by either compound was indicated by increases of immunoreactive renin associated with an increase of angiotensin I production rate of 67.8 +/- 33.6% after captopril and a decrease of 79.5 +/- 16.4% after Ro 42-5892. Furthermore, Ro 42-5892 decreased plasma renin activity by 64%. Whereas intra-arterial diastolic (60 +/- 5.1 to 51.4 +/- 7.2 mm Hg, p less than 0.01) and mean arterial (77.7 +/- 6.0 to 71.4 +/- 8.5 mm Hg, p less than 0.001) pressures decreased after captopril, they remained unchanged after Ro 42-5892. Captopril, but not Ro 42-5892, increased forearm blood flow (2.4 +/- 0.8 versus 1.9 +/- 0.8 ml/min/100 ml, p less than 0.01) and significantly enhanced the increase of forearm blood flow to brachial artery infusions of bradykinin (0.15, 1.5, 5, 15, and 50 ng/min/100 ml; 5 minutes each) from 744 +/- 632% to 1,383 +/- 514% (p less than 0.01). Furthermore, repeat bradykinin infusions resulted in further decreases of blood pressure (from mean pressure of 71.4 +/- 8.5 to 63.2 +/- 7.6 mm Hg, p less than 0.01) only after captopril. Changes of blood pressure after captopril were unrelated to baseline plasma renin activity but correlated with captopril-induced enhancement of vasodilation to bradykinin (r = 0.68, p less than 0.05). CONCLUSIONS. The lack of blood pressure effects of renin inhibition in contrast to angiotensin converting enzyme inhibition suggests that the renin-angiotensin system does not contribute significantly to blood pressure control in normotensive, sodium-replete subjects. The hypotensive activity of angiotensin converting enzyme inhibitors may result from additional hormonal effects, for example, inhibition of bradykinin degradation and/or subsequent increases of vasodilating prostaglandins or endothelium-derived relaxing factor(s).     

Plasma atrial natriuretic factor and cyclic GMP in mitral stenosis treated by balloon valvulotomy. Effect of atrial fibrillation

To study the relation between plasma atrial natriuretic factor (ANF) and cardiac pressures, we measured plasma ANF in 24 patients with mitral stenosis 30 minutes before and 20 minutes after balloon mitral valvulotomy. All patients were without physical signs of congestive heart failure. Normal sinus rhythm was present in 15 (group 1), whereas the other nine (group 2) had permanent atrial fibrillation. There were no significant differences between groups for basal mean pressures in right atrium (RA), left atrium (LA), and pulmonary artery (PA). Valvulotomy resulted in a fall in both groups (p less than 0.001) in LA and PA mean pressures, whereas heart rate, cardiac index, and RA and aorta (AO) pressures did not change significantly. Basal ANF was not different in either group in RA (240 +/- 43 vs. 266 +/- 35 pg/ml) or AO (441 +/- 92 vs. 643 +/- 70 pg/ml) but tended to be higher in group 2 in LA (428 +/- 88 vs. 682 +/- 84 pg/ml; p = 0.059) and PA (488 +/- 93 vs. 759 +/- 92 pg/ml; p = 0.057). Plasma ANF was the highest in PA, and about 50% ANF was extracted in the systemic circulation. After valvulotomy, plasma ANF was greater (p less than 0.05) in group 2 (372 +/- 90, 755 +/- 152, 805 +/- 134, and 707 +/- 144 pg/ml) than in group 1 (206 +/- 36, 386 +/- 47, 429 +/- 66, and 421 +/- 49 pg/ml), regardless of the site of blood collection (RA, LA, PA, and AO, respectively). PA ANF was correlated with LA pressure (p less than 0.05) in group 1 before as well as after valvulotomy, whereas there was no such correlation in group 2. Cyclic GMP (cGMP) in LA was correlated (p less than 0.01) with PA ANF in group 1, and LA cGMP (10.0 +/- 1.2 and 9.1 +/- 1.8 pmol/ml in groups 1 and 2, respectively) was higher (p less than 0.05) than PA cGMP (9.1 +/- 1.0 and 8.0 +/- 1.5 pmol/ml in groups 1 and 2, respectively) before valvulotomy, which suggests the presence of ANF receptors in the pulmonary circulation. Taken together, these results indicate that in patients in sinus rhythm with mitral stenosis, there is an increase in ANF secretion depending on LA pressure. ANF secretion is also high in patients with mitral stenosis and atrial fibrillation but does not respond appropriately to changes in LA pressure.(ABSTRACT TRUNCATED AT 400 WORDS)     

Contribution of prostaglandins to the antihypertensive action of captopril in essential hypertension

To determine whether prostaglandins contribute to the depressor response to the converting enzyme inhibitor, captopril, we measured the plasma prostaglandin levels by radioimmunoassy before and after captopril administration, and then examined the effect of prostaglandin synthetase inhibition on captopril's antihypertensive effect. When a single oral captopril dose (25-100 mg) was given to 31 sodium-restricted patients with essential hypertension, the levels of the stable transformation product of prostacyclin remained unmeasurable and that of thromboxane A2 did not change, while the metabolite of PGE2 (PGE-M) increased by 53% (34 +/- 4pg/ml pre-captopril, 52 +/- 5 pg/ml after; p less than 0.001). As expected, blood pressure (BP) and angiotension II (AII levels fell, and kinin levels rose (all changes p less than 0.001). We then blocked prostaglandin synthesis in 18 of these subjects for 24 hours with either indomethacin (n = 10) or aspirin (n = 8) before repeating the captopril dose, to assess the importance of these PGE-M increments. The PGE-M responses to captopril were effectively blocked in nine of 10 subjects receiving indomethacin and four of eight receiving aspirin. In these 13 patients, the depressor response to captopril was significantly blunted (-20 +/- 3mm Hg pre-synthetase inhibition vs - 13 +/- 2 mm Hg post; p less than 0.05). When these agents did not block the PGE-M response to captopril, the BP response was also unchanged (-15 +/- 4mm Hg pre, -18 +/- 5mm Hg post). Neither indomethacin nor aspirin changed the AII or kinin responses to captopril. We conclude that the prostaglandins may be important mediators of captopril's antihypertensive effect in the sodium-restricted state.     

Low-dose infusion of atrial natriuretic factor in mild essential hypertension

Intra-arterial blood pressure, cardiac output, heart rate, right heart indexes, urinary electrolytes, and urinary volume were monitored in eight patients with untreated (WHO Class I) essential hypertension. The patients were given synthetic atrial natriuretic factor (ANF) (99-126 alpha-hANP) at 1 and 2 pmol/kg/min in series (phases 1 and 2, 2 hours each dose) or vehicle (hemaccel) in random order on two separate occasions while on their usual diet. Arterial plasma ANF levels increased significantly from basal and time-matched placebo values from 25 +/- 2 and 28 +/- 3 pmol/l to 50 +/- 4 and 83 +/- 9 pmol/l at the end of phases 1 and 2, respectively (p less than 0.001). After 30 minutes during phase 2, systolic blood pressure decreased significantly by 20 +/- 4 mm Hg (p less than 0.001) from basal and time-matched placebo values and remained significantly reduced (-17 +/- 4 mm Hg, p less than 0.001) by the end of the recovery period (2 hours after infusions were completed). Pulmonary systolic blood pressure decreased by 5 +/- 1 mm Hg (phase 2, p less than 0.05). Cardiac output decreased by 0.5 +/- 0.1 l/min below baseline at the end of phase 2 of ANF infusion, whereas it increased significantly (p less than 0.02) by 0.6 +/- 0.1 l/min during vehicle infusion. Systemic diastolic, pulmonary diastolic, right atrial, and wedge pressures were not significantly changed during ANF or vehicle infusions, nor were pulmonary vascular resistance or heart rate altered. Systemic vascular resistance did not change significantly during both infusions, whereas during recovery, systemic vascular resistance decreased significantly after ANF infusion was discontinued (p less than 0.05). Microhematocrit levels increased dose dependently during ANF. The maximum increase was observed at the end of phase 2 (+4.7 +/- 1.7%), whereas the microhematocrit level decreased to -2.4 +/- 0.6% with vehicle (p less than 0.001) at the end of phase 2. Urinary sodium excretion increased significantly (p less than 0.02) by the end of phase 2 under ANF infusion (+38 +/- 15%), whereas it decreased (-10 +/- 6%) under placebo infusion by the end of phase 2. Urinary magnesium excretion was significantly increased during ANF infusion from phase 1 (p less than 0.02), whereas urinary potassium levels, calcium levels, creatinine levels, volume, and glomerular filtration rate did not differ significantly between the two infusions. Plasma renin, angiotensin II, aldosterone, and catecholamine concentrations did not change significantly during ANF or vehicle infusions.(ABSTRACT TRUNCATED AT 400 WORDS)     

Reversal of cardiac hypertrophy and fibrosis by S21402, a dual inhibitor of neutral endopeptidase and angiotensin converting enzyme in SHRs

OBJECTIVE: The major advantage of dual inhibitors of neutral endopeptidase (NEP) and angiotensin converting enzyme (ACE) is their ability to lower blood pressure irrespective of renin or volume status. The aim of this study was to determine whether dual NEP/ACE inhibition produces different effects on cardiovascular structure and fibrosis, hormonal parameters and inhibition of tissue enzymes compared with selective inhibition of ACE and NEP in the spontaneously hypertensive rat (SHR). METHODS: Male SHRs received the dual NEP/ACE inhibitor (S21402, 100 mg/kg per day), the ACE inhibitor (captopril, 50 mg/kg per day), the NEP inhibitor (SCH42495, 60 mg/kg per day) or vehicle for 2 weeks. RESULTS: S21402 produced equivalent blood pressure lowering effects to captopril (vehicle, 220 +/- 1 mmHg; S21402, 189 +/- 2 mmHg; captopril, 187 +/- 3 mmHg), but was a more effective antihypertensive agent than SCH42495 (214 +/- 2 mmHg, P< 0.01). All treatments reduced left ventricular mass (P< 0.05) and cardiac fibrosis (P< 0.01). S21402 inhibited renal NEP and ACE (P< 0.01), SCH42495 inhibited renal NEP (P < 0.01), and captopril inhibited renal ACE (P< 0.01). Captopril and S21402 increased plasma renin activity (P< 0.05), but the rise with S21402 was attenuated compared with that caused by captopril (P< 0.01). All treatments reduced plasma aldosterone levels (P< 0.01), and NEP inhibition with SCH42495 and S21402 increased plasma atrial natriuretic peptide (ANP; P< 0.05). CONCLUSIONS: These results indicate that selective NEP inhibition has major benefits in the regression of cardiac hypertrophy and reduction of fibrosis but has limited antihypertensive effects. The dual NEP/ACE inhibitor S21402 offered no advantage over the selective ACE inhibitor in terms of blood pressure reduction, or attenuation of cardiac hypertrophy and fibrosis, but did increase plasma ANP and blunted the reactive rise in renin with ACE inhibition. Further studies are needed to determine whether more complete blockade of the renin-angiotensin system with dual NEP/ACE inhibition results in additional benefits in terms of morbidity and mortality in cardiovascular disease.     

Responses of plasma bradykinin and the renin angiotensin axis to angiotensin II in hyperthyroid patients

The present investigation was undertaken to elucidate the possible interplay between the circulating kinin(s) and the renin angiotensin axis in hyperthyroidism. The responsiveness of plasma aldosterone (p-Ald), kinin (p-BK), plasma renin activity (PRA) and serum angiotensin converting enzyme activity (ACEA) to infusion of angiotensin II at a dose of 4, 8 and 16 ng/kg.min. was asessed in 15 hyperthyroid patients and 10 euthyroid controls. There was impaired angiotensin II induced response of blood pressure in hyperthyroid patients, and basal concentrations of p-Ald were 7.7 +/- 3.8 ng/dl in euthyroid controls and 12.6 +/- 3.1 ng/dl in hyperthyroid patients (p less than 0.05). As compared to the euthyroid controls, the hyperthyroid patients showed a reduced response of plasma aldosterone to angiotensin II infusion. Angiotensin II infusion increased p-BK from basal levels of 19.1 +/- 8.2 pg/ml to 31.0 +/- 7.8 pg/ml (p less than 0.05) only in hyperthyroid patients and did not increase ACEA in either group. Next, the effects of a single administration of captopril (50 mg p.o.) on blood pressure and p-BK in hyperthyroid patients and euthyroid controls were studied. In the two groups blood pressure was not changed by captopril, but p-BK increased significantly. The present results do not support the view that there may be a direct linkage between the kallikrein kinin system and the renin angiotensin axis mediated by kininase II or angiotensin converting enzyme in human peripheral blood. Also it is unlikely that kinin may play a role in the mechanism of reduced responsiveness of aldosterone and blood pressure to angiotensin II in hyperthyroidism.     

Effects of acute angiotensin converting enzyme inhibition on renal blood flow in patients with stable congestive heart failure

Renal blood flow was serially measured as the left renal vein blood flow using the continuous thermodilution technique during acute angiotensin converting enzyme inhibition in 20 patients with stable congestive heart failure. Eleven patients received captopril orally, and the remaining nine patients received enalaprilat intravenously. During the control period, left renal vein blood flow and cardiac output did not correlate closely (r = 0.57). Following administration of captopril or enalaprilat, stroke volume index increased from 20 +/- 7 to 25 +/- 8 ml/M2 (p less than 0.001), while pulmonary capillary wedge pressure decreased from 26 +/- 8 to 19 +/- 8 mm Hg (p less than 0.001). Left renal vein blood flow increased in all patients despite a consistent reduction in systemic arterial pressure. At peak effect, left renal vein blood flow increased from 295 +/- 86 to 443 +/- 122 ml/min (p less than 0.001), while mean systemic arterial pressure fell from 81 +/- 13 to 71 +/- 14 mm Hg (p less than 0.001). Thus, in patients with stable congestive heart failure, acute angiotensin converting enzyme inhibition, although decreasing substantially systemic arterial pressure, consistently enhances renal blood flow.     

Coronary vasodilatation and improved myocardial lactate metabolism after angiotensin converting enzyme inhibition with cilazapril in patients with congestive heart failure.

The effects of angiotensin converting enzyme inhibition on systemic and coronary hemodynamics and on myocardial lactate metabolism were investigated before and 2 and 6 hours after cilazapril at rest and during supine submaximal exercise in 10 patients with New York Heart Association class II or III chronic congestive heart failure. Angiotensin converting enzyme inhibition, indicated by a significant increase in plasma renin activity, resulted in significant reductions in blood pressure and systemic vascular resistance. Myocardial oxygen demand decreased (resting double product 10.9 +/- 3.7 vs 12.2 +/- 3.8 mm Hg beats/min 10(-3); p less than 0.05), but coronary sinus blood flow remained unchanged and calculated coronary resistance decreased (0.45 vs 0.5 units, rest 6 hours; p less than 0.05) suggesting coronary vasodilatation. Changes in coronary vascular resistance were directly related to changes in systemic vascular resistance (r = 0.75, p less than 0.5). Myocardial lactate extraction increased at rest (47 +/- 60 vs 134 +/- 132 mumol/min; p less than 0.5) and during exercise (27 +/- 54 vs 491 +/- 317 mumol/min; p less than 0.05) both in patients with coronary artery disease (n = 5) and idiopathic dilated cardiomyopathy (n = 5). Resting lactate production was converted to lactate extraction in two patients with coronary artery disease. Neither plasma catecholamine nor atrial natriuretic peptide concentrations changed significantly. The results suggest coronary vasodilation and improved aerobic myocardial metabolism by angiotensin converting enzyme inhibition in patients with congestive heart failure.     

Hemodynamic and renal responses to physiological levels of atrial natriuretic factor in conscious dogs

The effects of increases in plasma atrial natriuretic factor (ANF) similar to those encountered after rapid volume expansion were examined in conscious dogs. Hemodynamics and renal function were continuously monitored during 30 minutes of human ANF infusion (10 ng/kg.min) and throughout a 30-minute recovery period. Ten minutes into the infusion period, plasma levels of ANF were elevated (p less than 0.01) by 34 +/- 9 from 36 +/- 5 pg/ml and sodium excretion increased (p less than 0.05) by 34 +/- 7 from 67 +/- 9 mueq/min. At that time, urine flow did not differ from baseline (0.25 +/- 0.03 ml/min). Renal blood flow velocity fell (p less than 0.01) by 5.0 +/- 0.5 from 42.3 +/- 3.7 cm/sec. Thirty minutes into the infusion period, plasma ANF levels were increased (p less than 0.01) by 61 +/- 9 pg/ml, similar to levels found after rapid volume expansion in conscious dogs. Urine flow and sodium excretion were elevated (p less than 0.01) by 0.35 +/- 0.06 ml/min and by 65 +/- 12 mueq/min, respectively. Renal blood flow velocity was reduced (p less than 0.05) by 4.4 +/- 1.5 cm/sec. Neither right atrial pressure, left ventricular end-diastolic pressure, mean arterial pressure, the first derivative of left ventricular pressure over time (dP/dt), nor heart rate were influenced by the elevated ANF plasma levels. Circulating levels of vasopressin and aldosterone were unaltered by these increases in plasma ANF. Thirty minutes into the recovery period, all variables were similar to the preinfusion baseline. Thus, in conscious dogs, physiologically relevant increases in plasma levels of ANF reached diuretic and natriuretic thresholds.(ABSTRACT TRUNCATED AT 250 WORDS)     

Systemic hypertension after cardiac transplantation: effect of cyclosporine on the renin-angiotensin-aldosterone system

Fifteen patients who had undergone cardiac transplantation and who had hypertension (164 +/- 14/112 +/- 13 mm Hg), aged 16 to 57 years (mean 39), were treated with cyclosporine, 8 +/- 3 mg/kg/day, and prednisolone, 0.27 +/- 0.1 mg/kg/day, for 63 to 788 days (mean 288) after transplantation. They were not given antihypertensive drugs. Before treatment, the mean urinary sodium level was 104 +/- 48 mEq/day. Two discrete abnormalities accompanied their high blood pressure (BP): an increase in serum creatinine levels (p less than 0.05) to values exceeding those measured just before transplantation (2.1 +/- 1.0 vs 1.35 +/- 0.54 mg/dl) with low creatinine clearance (61 +/- 28 ml/min X 1.73 m2), and a 15% increase in plasma volume (+445 +/- 686 ml, p less than 0.02). Urinary excretion of vanilmandelic acid and total metanephrines was normal. Supine plasma renin activity was also normal (0.78 +/- 0.32 nmol/ml/hour). The stimulation of renin release after acute inhibition of converting enzyme by captopril was less marked than is usual in hypertensive subjects (0.86 +/- 0.54 nmol/liter/hour). Captopril induced a smaller drop in BP than nifedipine (-8 +/- 13/-6 +/- 10 mm Hg vs -14 +/- 11/-15 +/- 10 mm Hg). Levels of plasma aldosterone, angiotensinogen and converting enzyme activity were all normal, 308 +/- 147 pmol/liter, 712 +/- 164 nmol/ml and 30 +/- 6 mU/ml, respectively. It is concluded that hypertension is common in cardiac transplantation patients treated with cyclosporine, since 13 of our 15 subjects were normotensive before transplant.(ABSTRACT TRUNCATED AT 250 WORDS)     

Identification of hyponatremia as a risk factor for the development of functional renal insufficiency during converting enzyme inhibition in severe chronic heart failure

To identify patients with severe chronic heart failure who are at greatest risk of developing functional renal insufficiency during converting enzyme inhibition, creatinine clearance was measured in 59 patients before and after long-term therapy with captopril (39 patients) or enalapril (20 patients), while digitalis and diuretic therapy was kept constant. Creatinine clearance increased or remained constant in 33 of the 59 patients (Group I), but declined in the remaining 26 patients (Group II). The two groups were similar with respect to the cause of heart failure, pretreatment renal function and all pretreatment hemodynamic variables. Patients in Group II, however, had lower values for serum sodium concentration (134.8 +/- 1.0 versus 137.0 +/- 0.6 mmol/liter) and higher values for plasma renin activity (10.6 +/- 3.4 versus 3.0 +/- 0.5 ng/ml per hour), received larger doses of furosemide (108 +/- 11 versus 84 +/- 6 mg/day), were more frequently diabetic (42 versus 15%) and were more frequently treated with enalapril (50 versus 21%) than were patients in Group I (all p less than 0.05). By stepwise logistic analysis, only hyponatremia (or an elevated plasma renin activity) and enalapril therapy independently predicted the decline in creatinine clearance during converting enzyme inhibition. These observations could not be explained by changes in systemic blood pressure. In patients with a normal serum sodium concentration (greater than or equal to 137 mmol/liter), creatinine clearance increased with captopril (+21%, p less than 0.05), but not with enalapril (-6%, p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)     

EC 24.11 inhibition in man alters clearance of atrial natriuretic peptide.

Metabolic clearance and the biological effects of exogenous human atrial natriuretic factor (ANF) were assessed in two groups each of eight normal volunteers receiving 2-h iv infusions of ANF (2.5 pmol/kg.min) on the fifth day of dosing with the orally active inhibitor of endopeptidase 24.11, candoxatril (25 mg every 12 h in group 1 and 100 mg every 12 h in group 2), and placebo in balanced randomized, double blind, placebo-controlled, cross-over experiments. Although 4 days of pretreatment with the endopeptidase inhibitor did not affect basal plasma ANF, candoxatril enhanced mean ANF-induced increases in plasma ANF by 27 pmol/L (P = NS) and 42 pmol/L (P less than 0.002) in groups 1 and 2, respectively. Calculated MCRs for ANF were significantly reduced by both doses of candoxatril [group 1, 2.5 +/- 0.4 vs. 4.3 +/- 0.6 L/min (P less than 0.01); group 2, 2.3 +/- 0.4 vs. 5.6 +/- 0.8 L/min (P less than 0.001)]. ANF significantly enhanced urinary sodium excretion above preinfusion values in both study phases in both groups. Candoxatril significantly further augmented natriuresis in group 2 (P less than 0.01), but not group 1. Inulin clearance was minimally enhanced, and para-aminohippuran clearance was slightly decreased by candoxatril in both groups. Neither effect alone was statistically significant, but derived renal filtration fractions were significantly enhanced in both groups [group 1, 15.5 +/- 0.5% vs. 13.9 +/- 0.6% (P less than 0.01); group 2, 19.3 +/- 1.9% vs. 18.0 +/- 2.7% (P less than 0.01)]. Basal and stimulated cGMP concentrations in both plasma and urine were significantly enhanced by candoxatril in the two groups (P less than 0.001 and P less than 0.01, respectively, for combined data). Urinary ANF immunoreactivity was significantly enhanced by candoxatril in both groups (P less than 0.05 and P less than 0.01 in groups 1 and 2, respectively), with a more pronounced effect evident at the higher dose (P less than 0.01). These results show that chronic pretreatment with an endopeptidase inhibitor in normal man causes a dose-related reduction in the metabolic clearance of exogenous ANF, amplifies cGMP, and increases renal filtration and the natriuretic responses to infused ANF.     

Pulmonary extraction and left atrial secretion of atrial natriuretic factor during cardiopulmonary bypass surgery.

We have investigated the role of the lungs in the extraction of atrial natriuretic factor (ANF) by measuring plasma levels in samples taken from the central circulation in 12 patients (mean age 59 years; range 43 to 68) undergoing cardiac surgery. We also investigated the effects of cardiopulmonary bypass on ANF levels. ANF levels (mean +/- SD) were lower in pulmonary venous samples (41 +/- 20 pg/ml) than in pulmonary arterial samples (54 +/- 18 pg/ml; p less than 0.001), demonstrating 24% extraction of ANF by the lungs. Both left atrial (47 +/- 23 pg/ml) and systemic arterial levels (52 +/- 22 pg/ml) were higher than pulmonary venous levels (both p less than 0.05), indicating secretion of ANF into the left side of the heart. During cardiopulmonary bypass, plasma ANF concentration fell from 68 +/- 23 pg/ml before aortic cross-clamping to 35 +/- 13 pg/ml 10 minutes after and 28 +/- 9 40 minutes after the application of clamps (both p less than 0.001). A rebound rise to 122 +/- 33 pg/ml followed the release of the clamp (p less than 0.001). This study demonstrates that ANF is extracted by the lungs and secreted directly into the left side of the heart. The considerable fall in plasma levels that was observed during aortic cross-clamping might contribute to the neurohumoral activation and increased peripheral resistance observed after prolonged cardiopulmonary bypass and to the risk of renal ischemic injury.     

Effect of atrial natriuretic factor on coronary vascular tone

To test whether atrial natriuretic factor (ANF) may be involved in the modulation of coronary vasomotor tone, ANF was injected into angiographically normal left coronary arteries. Measurement of epicardial diameters of the circumflex (Cx) and left anterior descending artery (LAD) were made from biplane angiograms by an automatic contour-detection system. Bolus injection of ANF (0.07 micrograms/kg, diluted in 1 ml 0.9% NaCl, n = 7) increased diameter of proximal segments of LAD (11 +/- 4%) and Cx (10 +/- 4%) (p less than 0.02 each vs control) without altering heart rate and mean arterial pressure (MAP). Intracoronary nitroglycerin (NTG, 0.3 mg) increased diameters of identical LAD and Cx segments by 18 +/- 3% and 20 +/- 4%. Intracoronary ANF infusion (0.02 micrograms/kg/min over 5 min, followed by 0.1 micrograms/kg/min, n = 10) exerted dose-dependent increases in diameters of LAD and Cx (low dose: + 5 +/- 2%, p less than 0.05 vs control; high dose: + 13 +/- 3%, p less than 0.01 vs control). ANF-infusion increased arterial plasma ANF levels from 280 +/- 80 pg/ml during control to 894 +/- 82 pg/ml (low dose; + 614 pg/ml vs control) and to 2290 +/- 228 pg/ml (high dose). Severe ischemia in four patients undergoing angioplasty exerted substantial increase in arterial ANF levels (160 +/- 60 to 608 +/- 111 pg/ml; + 448 pg/ml vs control), similar to the increase elicited by low dose ANF infusion in man.(ABSTRACT TRUNCATED AT 250 WORDS)     

Blood glucose control determines the renal haemodynamic response to angiotensin converting enzyme inhibition in type 1 diabetes

Elevation of glomerular filtration rate (GFR) is a feature of diabetes mellitus in humans and in animal models. Angiotensin II has been implicated as a mediator of GFR in diabetes. The acute effect of inhibition of angiotensin converting enzyme with captopril on renal haemodynamic and endocrine parameters was therefore studied in 14 normotensive male Type 1 diabetic patients, and the responses compared with those in five normal male control subjects. Following captopril 12.5 mg orally the diabetic patients exhibited an acute fall in GFR from 122 +/- 3.8 to 113 +/- 4.5 ml min-1 1.73-m-2 (p less than 0.02) and a rise in renal plasma flow (RPF) from 670 +/- 57 to 797 +/- 46 ml min-1 1.73-m-2 (p less than 0.01) which resulted in a fall in filtration. This did not occur in normal control subjects. Natriuresis occurred only in normal control subjects. There was no change in urinary excretion of PGE2 or kallikrein in either group but excretion of 6-keto-PGF1 alpha fell in the diabetic patients. There was a significant correlation between glycosylated haemoglobin and baseline RPF (rs = -0.79, p less than 0.001) and filtration fraction (rs = 0.83, p less than 0.001) that persisted when the change in these variables following captopril was analysed. Our results are compatible with the response to ACE inhibition in diabetic patients being secondary to inhibition of angiotensin II and suggest that this response may be related to blood glucose control.     

Renal and endocrine responses to a renin inhibitor, enalkiren, in normal humans

Interpretation of renin-angiotensin blockade with angiotensin converting enzyme inhibitors is potentially confounded by their multiple effects. We used a selective renin inhibitor (enalkiren, A-64662) to explore the renal and endocrine effects of angiotensin II in healthy men. Each received 90-minute enalkiren infusions at 2-day intervals, on a low (10 mmol, 16 subjects) and high (200 mmol, 12 subjects) salt diet. Plasma renin activity, immunoreactive plasma angiotensin II and aldosterone concentrations, inulin, and p-aminohippurate clearance were measured by standard methods. Plasma renin activity fell at 0.1 micrograms/kg, but the threshold for biologic effect was 256 micrograms/kg, where plasma immunoreactive angiotensin II and aldosterone concentration fell, and renal plasma flow rose (p less than 0.01). The maximal renal vascular response (+152 +/- 23 ml/min/1.73 m2) occurred at 512 micrograms/kg (p less than 0.01). Diastolic and mean blood pressure fell modestly but significantly (p less than 0.05). Responses were limited on a high salt diet. We confirm that conventional plasma renin activity measurement is misleading in humans receiving a renin inhibitor. The renal vascular response to renin inhibition in this study appeared to substantially exceed reported responses to angiotensin converting enzyme inhibition, perhaps reflecting a crucial and relatively inaccessible intrarenal locus.     

Effect of captopril on 99mTc-diethylenetriaminepentaacetic acid renograms in two-kidney, one clip hypertension

In an effort to improve on the noninvasive detection of renal artery stenosis, we investigated the effect of angiotensin converting enzyme inhibition on computer-assisted 99mTc-diethylenetriaminepentaacetic acid (DTPA) renal flow studies in a canine model of two-kidney, one clip hypertension and compared these findings with clearances of inulin and p-aminohippuric acid in the stenotic and contralateral kidney before and after converting enzyme inhibition. The 99mTc-DTPA renal flow study with the converting enzyme inhibitor captopril (1.5 mg/kg bolus with 1.5 mg/min infusion) showed an increased sensitivity in the detection of unilateral renal artery stenosis over the use of the 99mTc-DTPA study alone. Captopril induced striking alterations that were most evident in the 15-minute 99mTc-DTPA renal flow study, in which all nine curves exhibited severely blunted uptake and excretion of the radionuclide. These changes were reversed during a recovery study without converting enzyme inhibition and were not seen when blood pressure was lowered with nitroprusside to a level similar to that observed during converting enzyme inhibition. The changes shown by the 99mTc-DTPA study during converting enzyme inhibition correlated with a decrease in the glomerular filtration rate of the stenotic kidney. Captopril infusion significantly decreased the glomerular filtration rate of the stenotic kidney (16.0 +/- 3.1 vs 11.0 +/- 2.5 mg/min, p less than 0.03) but not of the contralateral kidney (32.4 +/- 2.6 vs 28.4 +/- 2.8 mg/min).(ABSTRACT TRUNCATED AT 250 WORDS)